P2D Inc. is developing a synthetic melatonin agonist, PD6735, for the treatment of depression. Preliminary Studies indicate that PD6735 produces an antidepressant-like effect in rodents. Additional preclinical studies indicate that PD6735 is safe and is a high-affinity agonist at MT1 and MT2 receptors. The goal of this Phase 1 SBIR proposal is to determine PD6735 efficacy in two widely employed rodent models of depression. Preliminary Studies indicate that the PD6735 and the antidepressant imipramine produce similar antidepressant-like effects in a preclinical model of depression, open filed. We propose to extend our Preliminary Studies and determine PD6735 efficacy in two widely employed models of depression: 1) the forced swim test (Porsolt test), and 2) the chronic mild stress model of depression. In both models we will also employ the tricyclic antidepressant imipramine and the selective serotonin uptake inhibitor (SSRI) fluoxetine as positive comparators. Additionally, the antidepressant effect of melatonin will be determined. Our Specific Aims are: Specific Aim 1: Determine the antidepressant activity of acute and chronic administration of the melatonin agonist PD6735 in the forced swim test preclinical model of depression (Porsolt test) in rats. Specific Aim 2: Determine the antidepressant activity of acute and chronic administration of the melatonin agonist PD6735 in the chronic mild stress model of depression in rats. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page This application proposed to determine if our proprietary melatonin agonist, PD6735, demonstrates antidepressant efficacy in preclinical models of depression. About 10% of all men in America and up to 25% of all women will experience depression in their lifetime according to the National Institute of Mental Health. In the United States, depression is responsible for up to 70% of all psychiatric hospitalizations and about 40% of suicides. The cost of depression in the United States was estimated by NIMH to be $83 billion including both $26 billion in costs of treatment and $57 billion in losses such as absenteeism, reduced productivity at work and the value of lifetime earnings due to suicide-related deaths. [unreadable] [unreadable] [unreadable]